Treatment of diabetic kidney disease

INTRODUCTION — Chronic kidney disease (CKD) is common in people with both type 1 and type 2 diabetes. It is defined by the presence of reduced glomerular filtration rate (GFR) and/or increased urinary albumin excretion for at least three months (table 1). (See "Definition and staging of chronic kidney disease in adults", section on 'Definition of CKD'.)

Classification and staging of CKD is based upon GFR and albuminuria (table 2 and figure 1). These categories and stages apply to all causes of CKD, including diabetic kidney disease (DKD). Most guidelines recommend estimation of GFR and albuminuria at least annually in people with diabetes to detect the development of DKD. (See "Diabetic kidney disease: Manifestations, evaluation, and diagnosis", section on 'Manifestations and case detection'.)

Globally, DKD is a major cause of CKD and is the most common cause of end-stage kidney disease (ESKD). As an example, in the United States in 2017, diabetes was reported as a primary etiology in nearly one-half of all patients diagnosed with ESKD [1].

The management of individuals with DKD is discussed here (algorithm 1). The pathophysiology, epidemiology, natural history, evaluation, and diagnosis of DKD are presented separately:

●(See "Diabetic kidney disease: Pathogenesis and epidemiology".)

●(See "Diabetic kidney disease: Manifestations, evaluation, and diagnosis".)

Other management issues in patients with diabetes are discussed separately:

●(See "Overview of general medical care in nonpregnant adults with diabetes mellitus".)

●(See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus".)

●(See "Management of persistent hyperglycemia in type 2 diabetes mellitus".)

●(See "Treatment of hypertension in patients with diabetes mellitus".)

MANAGEMENT OF DIABETIC KIDNEY DISEASE (DKD)

General measures applicable to all patients with DKD — The general approach to all people with diabetes is also appropriate for people with diabetic kidney disease (DKD), although there are some specific considerations (algorithm 1).

Blood pressure control — We recommend blood pressure lowering in patients with DKD to levels below 130/80 mmHg (table 3). In general, this level of blood pressure control in patients with chronic kidney disease (CKD) reduces mortality and prevents cardiovascular morbidity. Additionally, intensive blood pressure lowering slows CKD progression among those with severely increased albuminuria (measured or estimated urine albumin excretion ≥300 mg/day). The evidence supporting our recommendation is presented separately:

●(See "Goal blood pressure in adults with hypertension", section on 'Patients with chronic kidney disease'.)

●(See "Goal blood pressure in adults with hypertension", section on 'Patients with diabetes mellitus'.)

Initial antihypertensive therapy in patients with DKD typically consists of either an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) titrated to maximally tolerated doses but not both simultaneously. The supporting data are discussed below and elsewhere:

●(See 'Severely increased albuminuria: Treat with angiotensin inhibition' below.)

●(See "Treatment of hypertension in patients with diabetes mellitus".)

●(See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Effect of renin-angiotensin system inhibitors on progression of CKD'.)

Combination antihypertensive therapy is required for most individuals with DKD. In such cases, the combination of an ACE inhibitor or ARB plus a dihydropyridine calcium channel blocker is often preferred [2]; however, a nondihydropyridine calcium channel blocker or diuretic may be preferred, rather than a dihydropyridine calcium channel blocker, in patients with severely increased albuminuria. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Calcium channel blockers'.)

As discussed in detail below, the combination of an ACE inhibitor plus an ARB should not be used. Similarly, simultaneous therapy with a renin inhibitor plus either an ACE inhibitor or ARB should be avoided. (See 'Type 2 diabetes: Treat with additional kidney-protective therapy' below.)

Glycemic control — In patients with type 1 diabetes, high-quality data suggest that intensive blood glucose control may prevent the development of DKD [3,4], and more limited data support the strategy of intensive glucose control in patients with kidney disease [5,6]. Consequently, the glycemic control target in patients with type 1 diabetes and DKD is ideally a glycated hemoglobin (A1C) of 7 percent or less, although the goal should be tailored to the individual, balancing the improvement in microvascular complications with the risk of hypoglycemia. However, glycemic targets in type 1 diabetes have not been well studied in patients with advanced CKD. The evidence for this approach is presented elsewhere. (See "Glycemic control and vascular complications in type 1 diabetes mellitus".)

The approach (to target an A1C of 7 percent or less, if tolerated) is similar in patients with type 2 diabetes, although fewer supportive data are available than for type 1 diabetes [7]. Glycemic targets in patients with type 2 diabetes are discussed elsewhere. (See "Glycemic control and vascular complications in type 2 diabetes mellitus".)

The risk of hypoglycemia with intensive glucose control is greater among patients with reduced glomerular filtration rate (GFR) [8-10]. This issue is presented elsewhere. (See "Hypoglycemia in adults with diabetes mellitus".)

A separate issue is that certain glucose-lowering medications should be avoided or used at a reduced dose in patients with DKD, depending upon the degree of reduced kidney function [11]. This issue is discussed separately. (See "Management of hyperglycemia in patients with type 2 diabetes and advanced chronic kidney disease or end-stage kidney disease".)

Other — In addition to blood pressure and glucose control, all patients with DKD should be counseled on lifestyle modification, and most should be treated with a statin:

●Lifestyle modification – Patients with diabetes, regardless of the presence of kidney disease, should be counseled on healthy eating, regular exercise, and if needed, weight loss and smoking cessation. (See "Nutritional considerations in type 2 diabetes mellitus" and "Exercise guidance in adults with diabetes mellitus" and "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Multifactorial risk factor reduction'.)

●Lipid lowering – Most patients with DKD are at high cardiovascular risk and should therefore be treated with a statin (calculator 1). If statin therapy is initiated in patients with reduced kidney function, atorvastatin or fluvastatin are often preferred because they do not require dose adjustment based upon the GFR. However, statins have not been shown to reduce the risk of cardiovascular events or mortality in patients with ESKD and are not recommended in such patients. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Lipid management' and "Statins: Actions, side effects, and administration", section on 'Chronic kidney disease' and "Secondary prevention of cardiovascular disease in end-stage kidney disease (dialysis)", section on 'Lipid modification'.)

Severely increased albuminuria: Treat with angiotensin inhibition — In addition to the general measures discussed above, we treat most patients who have diabetes and severely increased albuminuria with an ACE inhibitor or an ARB (algorithm 1). Severely increased albuminuria is defined as a measured (eg, with a 24-hour urine collection) or estimated (eg, using a random urine albumin-to-creatinine ratio [ACR]) albumin excretion ≥300 mg/day. Combination therapy with both an ACE inhibitor and an ARB, or combining one of these drugs with a renin inhibitor, should be avoided.

In practice, the majority of patients with diabetes with hypertension and DKD are treated with an ACE inhibitor or ARB, even if severely increased albuminuria is absent (ie, even if urine albumin excretion is <300 mg/day). However, while these drugs are more beneficial than other antihypertensive agents in patients with albuminuric DKD, they do not have clear advantages over calcium channel blockers or diuretics among those without severely increased albuminuria. (See "Treatment of hypertension in patients with diabetes mellitus".)

Inhibition of the renin-angiotensin system (RAS) has been the cornerstone of the management of DKD for decades. This is based on high-quality randomized trials demonstrating reductions in the risk of kidney outcomes in high-risk individuals:

●The best data supporting angiotensin inhibition in patients with type 1 diabetes come from a trial of 409 adult participants who had urine protein excretion ≥500 mg/day and a serum creatinine ≤2.5 mg/dL (221 micromol/L) [12,13]. Patients were randomly assigned to captopril (25 mg three times daily) or placebo; additional antihypertensive drugs were then added as necessary, although calcium channel blockers and other ACE inhibitors were excluded (ARBs were not available at the time of the trial). At three years, captopril reduced the rate of death or ESKD (11 versus 21 percent), reduced the likelihood of doubling of serum creatinine (12 versus 21 percent), and slowed the annual loss of creatinine clearance (11 versus 17 percent per year). The beneficial response to captopril, which was seen in both hypertensive and normotensive patients, is consistent with smaller studies that suggested that antihypertensive therapy with an ACE inhibitor slowed the rate of progression in diabetic nephropathy [14,15].

●In type 2 diabetes, evidence comparing RAS inhibition with another antihypertensive drug comes from the Irbesartan Diabetic Nephropathy Trial (IDNT) [16]. In the IDNT, 1715 participants aged 30 to 70 years with type 2 diabetes, hypertension, urine protein excretion ≥0.9 g/day, and mean serum creatinine of 1.7 mg/dL (150 micromol/L) were randomly assigned to irbesartan (75 to 300 mg once daily), amlodipine (2.5 to 10 mg once daily), or placebo. Target systolic blood pressure was ≤135 mmHg, or 10 mmHg lower than the value at screening (if systolic blood pressure at screening ≥145 mmHg), and target diastolic blood pressure was ≤85 mmHg. At 2.6 years, the likelihood of a doubling of serum creatinine was lower with irbesartan (17 percent) compared with amlodipine (25 percent) and placebo (24 percent); in addition, irbesartan nonsignificantly reduced the incidence of ESKD (14 versus 18 percent with amlodipine and placebo) (figure 2). There was no difference among the groups with respect to cardiovascular endpoints or death. Patients assigned to placebo had a higher blood pressure throughout the trial than those assigned irbesartan; however, the blood pressure in the irbesartan and amlodipine groups were similar, and therefore the benefits from irbesartan were independent of attained blood pressure [17,18].

●The Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial assigned 1513 adults with type 2 diabetes, albuminuria >300 mg/day (median urinary ACR of approximately 1250 mg/g), and mean serum creatinine 1.9 mg/dL (168 micromol/L), to losartan (50 titrating up to 100 mg once daily) or placebo, both in addition to conventional antihypertensive therapy (but not ACE inhibitors) [19]. The incidence of ESKD at 3.4 years was lower with losartan (20 versus 26 percent), as was a doubling of serum creatinine (22 versus 26 percent). Unlike IDNT, there was no active comparator, and the mean blood pressure throughout the study was lower among those assigned losartan.

The three trials cited above enrolled patients with albuminuric DKD (measured or estimated urine albumin excretion ≥300 mg/day). Several large trials suggest that angiotensin inhibition decreases the risk of progression from normal-to-mildly increased albuminuria (formerly called "normoalbuminuria") to moderately increased albuminuria (formerly called "microalbuminuria") and from moderately increased albuminuria to severely increased albuminuria (formerly called "macroalbuminuria") [20,21]. However, no major trial has found that these drugs prevent ESKD among patients with nonalbuminuric DKD, particularly when compared with a different antihypertensive drug (ie, an active comparator). As an example, in the largest antihypertensive drug trial among patients with diabetes, over 11,000 patients with type 2 diabetes were randomly assigned to a two-drug antihypertensive combination (perindopril plus indapamide) or placebo [21]. The mean blood pressure during the trial in the active treatment group was 6/2 mmHg lower than in the placebo group, and it is not possible to determine the degree to which the reduction in albuminuria was due to the ACE inhibitor, thiazide-like diuretic, or lower blood pressure [22,23].

There are no proven differences in outcomes comparing ACE inhibitors with ARBs in trials among patients with diabetes or among broader populations [24-26]. Thus, in general, either agent can be used when treating patients with DKD.

However, although combining an ACE inhibitor and an ARB decreases albuminuria compared with either agent alone, combination therapy does not prevent kidney disease progression or death, and it increases the rate of serious adverse events. Combination therapy with an ACE inhibitor plus an ARB should therefore not be used in patients with DKD:

●The best data come from the Veterans Affairs Nephropathy in Diabetes study (VA NEPHRON-D), a randomized placebo-controlled double-blind trial performed in 1448 mostly male patients with diabetic nephropathy (mean estimated GFR [eGFR], 54 mL/min/1.73 m²; mean ACR, 852 mg/g) [27]. All patients received 100 mg/day of losartan and were then randomly assigned to placebo or lisinopril (10 to 40 mg/day as tolerated); the primary endpoint was a composite of a 50 percent eGFR decline (or more than 30 mL/min/1.73 m²), ESKD, or death. The trial was discontinued early after a median of 2.2 years because of safety concerns. The combination therapy and monotherapy groups had a similar rate of primary events (18.2 versus 21 percent). However, acute kidney injury requiring hospitalization or occurring during hospitalization was significantly more common with combination therapy (18 versus 11 percent), as was severe hyperkalemia (9.9 versus 4.4 percent).

●Additional data come from the diabetes subgroup of the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). The ONTARGET trial compared combination ramipril and telmisartan therapy with ramipril alone in 25,620 patients with vascular disease or diabetes [25,26]. In the subset of 3163 patients from ONTARGET with DKD, combination therapy was associated with a nonsignificantly higher incidence of ESKD or doubling of serum creatinine (5.3 versus 4.8 percent), and a similar death rate (2.3 versus 2.2 percent), as compared with monotherapy [28]. In addition, patients with DKD who received combination therapy had higher rates of acute kidney injury requiring dialysis (1.4 versus 0.8 percent). Other findings from the ONTARGET trial are presented in detail elsewhere. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Combination of ACE inhibitors and ARBs' and "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Combination of ACE inhibitors and ARBs'.)

Similarly, the use of aliskiren, a direct renin inhibitor, in combination with either an ACE inhibitor or ARB does not appear to preserve kidney function, and it increases the risk of adverse events [29].

Type 2 diabetes: Treat with additional kidney-protective therapy — In addition to the general measures discussed above plus the use of an ACE inhibitor (or ARB) in albuminuric patients, patients with type 2 diabetes and DKD should be treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors.

Among patients with type 2 diabetes who have measured or estimated albuminuria ≥30 mg/day despite an ACE inhibitor (or ARB) and an SGLT2 inhibitor (or if an SGLT2 inhibitor is not tolerated), we suggest treatment with a nonsteroidal selective mineralocorticoid receptor antagonist (MRA; specifically finerenone), where available, provided the patient has a serum potassium ≤5 mEq/L and eGFR ≥25 mL/min/1.73 m² (see 'General measures applicable to all patients with DKD' above and 'Severely increased albuminuria: Treat with angiotensin inhibition' above):

●SGLT2 inhibitors – We recommend treatment of most patients with type 2 diabetes and DKD with an SGLT2 inhibitor, regardless of the degree of glycemic control (algorithm 1) [30,31]. Initiating SGLT2 inhibitors should generally be avoided among patients with an eGFR <20 mL/min/1.73 m² although they can likely be continued safely among patients whose eGFR ultimately falls below 20 mL/min/1.73 m² [32]. If canagliflozin is used, the dose is 100 mg once daily. If dapagliflozin is used, the dose is 10 mg once daily.

SGLT2 inhibitors can prevent important kidney endpoints, including ESKD [31,33]. Although the relative risk reduction of kidney failure is similar among patients with and without severely increased albuminuria (measured or estimated urine albumin excretion ≥300 mg/day), the absolute risk reduction is greater among those with severely increased albuminuria, since such patients have a higher absolute risk of developing a major kidney event. Thus, our recommendation is stronger for those with severely increased albuminuria than for those with normoalbuminuria or moderately increased albuminuria. The rationale for our approach is presented in detail below.

●Nonsteroidal selective MRAs – Among patients with type 2 diabetes who have measured or estimated albuminuria ≥30 mg/day despite an ACE inhibitor (or ARB) and an SGLT2 inhibitor (or if an SGLT2 inhibitor is not tolerated), we suggest treatment with a nonsteroidal selective MRA, specifically finerenone, where available, provided the patient has a serum potassium ≤5 mEq/L and eGFR ≥25 mL/min/1.73 m². The starting dose of finerenone is 20 mg once daily if eGFR is ≥60 mL/min/1.73 m² and 10 mg once daily if eGFR is ≥25 to 60 mL/min/1.73 m². The serum potassium and creatinine should be measured four weeks after starting finerenone. If the starting dose was 10 mg once daily, the dose can be increased to 20 mg once daily four weeks later if serum potassium is ≤4.8 mEq/L and eGFR has not declined by more than 30 percent.

Finerenone reduces the progression of kidney function impairment and cardiovascular events in patients with type 2 diabetes and DKD, while not substantially impacting blood pressure and only slightly increasing serum potassium levels. Finerenone has been studied in patients taking maximally tolerated doses of ACE inhibitors or ARBs but has not been studied extensively in patients taking SGLT2 inhibitors plus maximally tolerated doses of ACE inhibitors or ARBs.

●Glucagon-like peptide 1 (GLP-1) receptor agonists – SGLT2 inhibitors have a weak glucose-lowering effect, particularly in patients with reduced eGFR, and therefore patients whose glycated hemoglobin is far from their goal are likely to require additional glucose-lowering therapy. Aside from SGLT2 inhibitors, the glucose-lowering drugs with the strongest evidence of benefit on cardiovascular and kidney outcomes in patients with preexisting cardiovascular or kidney disease are the GLP-1 receptor agonists [31]. Thus, in patients with type 2 diabetes and DKD who have not achieved glycemic control despite initial glucose-lowering therapy (which is typically metformin) and an SGLT2 inhibitor, a GLP-1 receptor agonist can improve glycemic control and may provide additional benefit [34-36]. GLP-1 receptor agonists are discussed below and in other topics. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus" and "Management of persistent hyperglycemia in type 2 diabetes mellitus" and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus".)

Our recommendations outlined above are consistent with guidelines from the American Diabetes Association (ADA) and the Kidney Disease Improving Global Outcomes (KDIGO) on the treatment of patients with DKD [37,38].

Among those with an eGFR >45 mL/min/1.73 m², SGLT2 inhibitors act by blocking reabsorption of glucose in the proximal tubule through SGLT2, which lowers the renal glucose threshold and leads to substantial glycosuria. The glycosuria is dependent upon kidney function, and therefore the magnitude of glycosuria and lowering of blood glucose is smaller among individuals with reduced kidney function.

SGLT2 inhibitors have additional effects on the kidney, and, given their weak glucose-lowering effect, these effects are likely independent of glycemic control. By blocking the cotransporter, they reduce sodium reabsorption, which is usually increased in patients with diabetes due to the excess tubular glucose load. The resulting natriuresis reduces intravascular volume and blood pressure, but it also increases the delivery of sodium to the macula densa. Increased sodium delivery to the macula densa normalizes tubuloglomerular feedback and thereby reduces intraglomerular pressure (ie, reduces glomerular hyperfiltration) through constriction of the abnormally dilated afferent arteriole [39]. This decrease in glomerular hyperfiltration can, hypothetically, slow the rate of progression of kidney disease (see "Diabetic kidney disease: Pathogenesis and epidemiology", section on 'Glomerular hyperfiltration'). A range of additional mechanisms may explain the benefits of SGLT2 inhibitors on kidney disease progression [40].

SGLT2 inhibitors reduce the risk of kidney disease progression among patients with DKD who are already taking ACE inhibitors (or ARBs) [33,41-47], as well as the incidence of cardiovascular disease [33]. Among patients with DKD and severely increased albuminuria, the best data come from three large trials:

●The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial compared canagliflozin (100 mg once daily) with placebo in 4401 diabetic patients with an eGFR between 30 and 89 mL/min/1.73 m² and urine ACR >300 mg/g (median, 927 mg/g) despite taking an ACE inhibitor or ARB [42]. At 2.6 years, canagliflozin reduced the incidence of ESKD (5.3 versus 7.5 percent), doubling of serum creatinine (5.4 versus 8.5 percent), hospitalization for heart failure (4.0 versus 6.4 percent), cardiovascular death (5.0 versus 6.4 percent), and all-cause mortality (7.6 versus 9.1 percent), although the effects on cardiovascular death and all-cause mortality were not separately statistically significant. The beneficial effects of canagliflozin on slowing kidney function decline appeared to be similar among those with baseline eGFR <30 mL/min/1.73 m² (ie, among trial participants whose eGFR fell to below 30 mL/min/1.73 m² between enrollment and initiation of study medication) [48].

●In the similarly designed Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, 4304 individuals with eGFR 25 to 75 mL/min/1.73 m² and urine ACR 200 to 5000 mg/g (median 950 mg/g) were randomly assigned to dapagliflozin (10 mg once daily) or placebo [49]. Approximately two-thirds of enrolled patients had type 2 diabetes; 98 percent were taking an ACE inhibitor or ARB. At 2.4 years, dapagliflozin reduced all-cause mortality (4.7 versus 6.8 percent), as well as the incidence of ESKD (5.1 versus 7.5 percent), and also reduced the risk of a 50 percent or greater decline in eGFR (5.2 versus 9.3 percent). The beneficial effect of dapagliflozin was similar in patients with DKD and in patients with other forms of kidney disease, reinforcing the concept that beneficial effects are independent of glycemic control. There were no differences between the treatment groups with respect to major adverse effects.

●In the Study of Heart and Kidney Protection with Empagliflozin (EMPA-KIDNEY) trial, 6609 patients with eGFR 20 to 44 mL/min/1.73 m² (regardless of albuminuria) or 45 to 89 mL/min/1.73 m² (if albumin-to-creatinine ratio was at least 200 mg/g) were randomly assigned to empagliflozin 10 mg daily or placebo [50]. Less than half (46 percent) of participants had diabetes. At two years, empagliflozin reduced the incidence of ESKD (3.3 versus 4.8 percent), the incidence of a sustained decline in eGFR to <10 mL/min/1.73 m² (3.5 versus 5.1 percent), and the incidence of a sustained decrease in eGFR of 40 percent or more (10.9 versus 14.3 percent). The risks of all-cause mortality (4.5 versus 5.1 percent) and nonfatal cardiovascular events (4.3 versus 4.6 percent) were similar between the groups. Effects were similar in patients with and without diabetes and regardless of the eGFR at the start of the study. The benefit from empagliflozin was larger in patients with albumin-to-creatinine ratio ≥300 mg/g and substantially less in patients with lower albumin excretion.

Numerous other large trials of SGLT2 inhibitors in patients with type 2 diabetes enrolled subsets of patients with mostly nonalbuminuric DKD [45,51-61]. A meta-analysis of 13 trials and more than 90,000 participants with and without preexisting CKD (including the CREDENCE, DAPA-CKD, and EMPA-KIDNEY trials) examined the effect of SGLT2 inhibitors on kidney disease progression, which was defined as a sustained 50 percent or greater decline in eGFR, need for maintenance dialysis, kidney transplantation, or a sustained decline in eGFR to <10 to 15 mL/min/1.73 m² [51]. Compared with placebo, SGLT2 inhibitors reduced the rate of kidney disease progression among patients with diabetes regardless of preexisting DKD (1.8 versus 3.8 percent; hazard ratio [HR] 0.62, 95% CI 0.56-0.68). Among those with preexisting DKD, SGLT2 inhibitors lowered the rate of kidney failure (defined as the need for maintenance dialysis, kidney transplantation, or a sustained decline in eGFR to <10 to 15 mL/min/1.73 m²) compared with placebo (5.2 versus 7.6 percent; HR 0.66, 95% CI 0.56-0.77).

The relative benefits from SGLT2 inhibitors were similar among patients with different baseline levels of albumin excretion. However, given that the rate of kidney disease progression is substantially higher in patients with severely increased albuminuria, the absolute benefits of SGLT2 inhibitor therapy are greater among those with higher levels of albuminuria, despite similar relative risks.

SLGT2 inhibitors also reduced the rates of major cardiovascular events among patients with established atherosclerotic cardiovascular disease regardless of whether patients had DKD [31,33,45,51,56,59]. These drugs also prevent heart failure hospitalization and death in patients who have heart failure with reduced ejection fraction. (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Clinical outcomes'.)

SGLT2 inhibitors increase the risk of genital infections by two- to fourfold; such infections primarily include vulvovaginal candidiasis, which occur in 10 to 15 percent of women taking these drugs. SGLT2 inhibitors are also associated with Fournier's gangrene in rare cases [62]. In addition, SGLT2 inhibitors can produce "euglycemic" diabetic ketoacidosis in type 1 diabetes (and more rarely in type 2 diabetes). Thus, patients with a prior history of or risk factors for genital infections may reasonably choose to not take an SGLT2 inhibitor. In patients with DKD who have a lower absolute risk for progression of kidney disease, and who also do not have established atherosclerotic cardiovascular disease or heart failure, the benefits and harms of taking an SGLT2 inhibitor may be more closely balanced. (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Adverse effects'.)

Activation of the mineralocorticoid receptor is associated with cardiovascular and kidney disease, putatively by stimulating inflammatory and fibrotic cascades [63]. Steroidal MRAs, such as spironolactone, reduce albuminuria in patients with DKD but often cause hyperkalemia in patients with reduced eGFR, particularly when ACE inhibitors or ARBs are also used. The nonsteroidal MRA finerenone also reduces albuminuria and has a smaller effect on the serum potassium [64,65]. The effects of finerenone on kidney disease progression were examined in two large trials:

●In the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial, 5734 patients with type 2 diabetes and either severely increased albuminuria or moderately increased albuminuria plus retinopathy were randomly assigned to finerenone (10 to 20 mg once daily) or placebo [66]. All patients were taking a maximal, or maximally tolerated, dose of an ACE inhibitor or ARB at baseline. At 2.6 years, finerenone decreased the incidence of a 40 percent or larger decline in eGFR (16.9 versus 20.3 percent) and nonsignificantly reduced the rates of all-cause mortality (7.7 versus 8.6 percent), and kidney failure (7.3 versus 8.3 percent), which included an eGFR <15 mL/min/1.73 m² or the need for chronic dialysis. Hyperkalemia occurred more frequently with finerenone (18.3 versus 9.0 percent), although only a small number of patients discontinued randomized therapy due to this complication (2.3 versus 0.9 percent).

●A similar trial tested the effects of finerenone in 7437 patients with diabetic kidney disease who had less severe kidney disease (moderately increased albuminuria with an eGFR 25 to 90 mL/min/1.73 m² or severely increased albuminuria with an eGFR >60 mL/min/1.73 m²) [67]. Compared with placebo, finerenone reduced the risk of heart failure hospitalization (3.2 versus 4.4 percent), and nonsignificantly lowered the rate of kidney failure (1.2 versus 1.7 percent) and all-cause mortality (9.0 versus 10.1 percent). Hyperkalemia was more common with finerenone (10.8 versus 5.3 percent).

In a pooled analysis of these two trials, finerenone lowered the risk of kidney failure (3.9 versus 4.6 percent; HR 0.84, 95% CI 0.71-0.99) and hospitalization for heart failure (3.9 versus 5.0 percent; HR 0.78, 95% CI 0.66-0.92) at a median of three years, and nonsignificantly reduced all-cause mortality (8.5 versus 9.4 percent; HR 0.89, 95% CI 0.79-1.00) [68].

The great majority of patients enrolled in these two trials were not simultaneously treated with an SGLT2 inhibitor, and the subgroup of patients who were was too small to determine with certainty whether or not finerenone provided additional benefit.

Another nonsteroidal MRA, esaxerenone, also reduces albuminuria in patients with DKD [69]. However, trials of esaxerenone report higher rates of hyperkalemia than those examining finerenone [69-71], and the effects of esaxerenone on mortality and ESKD are unknown.

The GLP-1 receptor agonist liraglutide reduced the incidence of a composite kidney endpoint (consisting of new onset of albuminuria >300 mg/day, doubling of serum creatinine, ESKD, or kidney death) in a large trial of patients with type 2 diabetes [72]. However, the effect was predominantly due to a reduction in new-onset albuminuria. Similarly, another GLP-1 receptor agonist dulaglutide slowed the rate of decline in eGFR and prevented worsening of albuminuria in trials of patients with type 2 diabetes with and without CKD [73,74]. Thus, if additional glucose-lowering therapy is required in a patient with DKD despite initial glucose-lowering therapy and an SGLT2 inhibitor, then we would prefer starting a GLP-1 receptor agonist. GLP-1 receptor agonists also reduce the rates of cardiovascular disease [31]. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Microvascular outcomes' and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)

By inhibiting dipeptidyl peptidase (DPP) 4, DPP-4 inhibitors prevent the deactivation of a variety of bioactive peptides, including GLP-1, thereby modestly increasing GLP-1 levels. However, unlike GLP-1 receptor agonists, DPP-4 inhibitors have not prevented the development or progression of kidney disease in patients with diabetes, nor do they have any cardiovascular benefits [75,76]. The use of DPP-4 inhibitors in patients with type 2 diabetes, including their safety and need for dose adjustments in the setting of CKD, is discussed separately. (See "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus".)

A large trial of more than 5000 individuals with type 2 diabetes treated with metformin monotherapy directly compared the kidney effects of the GLP-1 receptor agonist liraglutide with a DDP-4 inhibitor, insulin, and glimepiride [77]. There were no significant differences among the groups at five years in terms of eGFR decline or development of CKD in this low-risk group. The patients enrolled had normal kidney function and well controlled blood pressure at baseline, and the number of events was small. As an example, despite the large study population, only 65 patients had a decline in kidney function of more than 40 percent to an eGFR <60 mL/min/1.73m². This study does not support the use of expensive GLP-1 receptor agonists for kidney protection in patients at low risk.

Therapies of limited use — Various other approaches have been studied as methods to slow the progression of DKD. However, there are insufficient data to advocate their use:

●Dietary protein restriction – The role of dietary protein restriction is unclear in patients with diabetes, particularly since such patients are often being treated with fat and simple carbohydrate restriction. Data are conflicting as to whether protein restriction can slow the progression of kidney disease [78-80]. In addition, it is uncertain whether a low-protein diet is significantly additive to other measures aimed at preserving kidney function, such as ACE inhibition and aggressive control of blood pressure and blood glucose [78].

●Medications and supplements – Other agents, some experimental and others in clinical use for other indications, have also been studied, including endothelin receptor antagonists, bardoxolone methyl, pentoxifylline, protein kinase C inhibitors, fenofibrate (a peroxisome proliferator-activated receptor [PPAR]-alpha specific ligand), silymarin (an herbal drug with antioxidant properties used in patients with hepatic disease), Janus kinase (JAK) 1 and 2 inhibitors, and fish oil [81-99].

MONITORING DURING THERAPY — Patients with diabetic kidney disease (DKD) should ideally be monitored every three to six months, with assessments of blood pressure, volume status, estimated glomerular filtration rate (eGFR) based on serum creatinine, serum potassium, glycated hemoglobin (A1C), and an evaluation of urine albumin or total protein excretion (usually a random urine albumin-to-creatinine ratio [ACR]). Other aspects of monitoring should be based upon the clinical situation. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers".)

In addition, it is prudent to assess the serum creatinine and potassium within one to two weeks of starting or intensifying renin-angiotensin system (RAS) inhibition [100]. Blood pressure should be assessed within one to two weeks of initiating or intensifying these agents.

An elevation in serum creatinine of as much as 30 to 35 percent above baseline that stabilizes within the first two to four months of therapy is considered acceptable and not a reason to discontinue therapy with these drugs [101-107]. In addition, among patients who are on chronic treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), the drug does not need to be discontinued if the eGFR declines to below 30 mL/min/1.73 m² [108].

Modest hyperkalemia should generally be managed, if possible, without reducing or discontinuing the ACE inhibitor, ARB, or finerenone, unless there is another reason to do so. If discontinued for hyperkalemia, the ACE inhibitor or ARB should be resumed as soon as it is safe to do so. Finerenone can be resumed if serum potassium is ≤5 mEq/L at a dose of 10 mg once daily, and the dose can be increased to 20 mg once daily if serum potassium, four weeks later, is ≤4.8 mEq/L. (See "Treatment and prevention of hyperkalemia in adults", section on 'Patients who can have the serum potassium lowered slowly'.)

Similarly, the serum creatinine, serum potassium, and blood pressure, plus the patient's volume status, should generally be ascertained within a few weeks of commencing a sodium-glucose cotransporter 2 (SGLT2) inhibitor. (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Hypotension'.)

Both RAS inhibition and SGLT2 inhibitors may increase the risk of symptomatic hypotension, and other antihypertensive therapies should be withdrawn first (if possible) before considering cessation of these evidence-based therapies. Similarly, SGLT2 inhibitors may cause volume depletion, and withdrawal or reduction of thiazide or loop diuretics should be attempted before discontinuing the SGLT2 inhibitor.

Reasons for referral of patients with DKD to a specialist nephrology service are similar to those for patients with other causes of chronic kidney disease (CKD), including advanced CKD (eGFR <30 mL/min/1.73m²), heavy albuminuria, rapid loss of kidney function, resistant hypertension, evidence of an inflammatory kidney disease (eg, hematuria and/or sterile pyuria), and difficult-to-manage complications of CKD (eg, hyperkalemia, anemia). (See "Definition and staging of chronic kidney disease in adults", section on 'Referral to a specialist'.)

PROGNOSIS — A substantial proportion of people with diabetic kidney disease (DKD) will have progressive loss of kidney function and will develop end-stage kidney disease (ESKD). The strongest risk factor for risk of progression is the presence of increased albuminuria, while people with reduced estimated glomerular filtration rate (eGFR) or anemia are also at increased risk. With available protective therapies, a dramatic stabilization of kidney function is likely to be achievable. (See "Diabetic kidney disease: Manifestations, evaluation, and diagnosis", section on 'Natural history'.)

Of note, people with DKD are at particularly high risk of cardiovascular events, and most have a higher risk of death (mostly cardiovascular) than developing kidney failure. Cardiovascular protective therapies are therefore also critical. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Reducing the risk of macrovascular disease'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults" and "Society guideline links: Chronic kidney disease in adults" and "Society guideline links: Diabetic kidney disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic (see "Patient education: Diabetic kidney disease (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●The general approach to all people with diabetes is also appropriate for people with diabetic kidney disease (DKD); specific considerations include (algorithm 1) (see 'General measures applicable to all patients with DKD' above):

•Intensive blood pressure lowering is appropriate in patients with DKD (table 3). The evidence supporting our recommendation is presented separately. (See "Goal blood pressure in adults with hypertension", section on 'Patients with chronic kidney disease' and "Goal blood pressure in adults with hypertension", section on 'Patients with diabetes mellitus' and 'Blood pressure control' above.)

•The glycemic control target in patients with type 1 diabetes and DKD is ideally a glycated hemoglobin (A1C) of 7 percent or less, although the goal should be tailored to the individual, balancing the improvement in microvascular complications with the risk of hypoglycemia. However, glycemic targets in type 1 diabetes have not been well studied in patients with advanced chronic kidney disease (CKD). The approach (to target an A1C of 7 percent or less, if tolerated) is similar in patients with type 2 diabetes, although fewer supportive data are available than for type 1 diabetes. The evidence for these approaches is presented elsewhere. (See "Glycemic control and vascular complications in type 1 diabetes mellitus" and "Glycemic control and vascular complications in type 2 diabetes mellitus" and 'Glycemic control' above.)

•In addition to blood pressure and glucose control, all patients with DKD should be counseled on lifestyle modification and most should be treated with a statin. (See 'Other' above.)

●In patients with type 1 or type 2 diabetes who have DKD and severely increased albuminuria, we recommend an antihypertensive regimen that includes an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) (Grade 1B) (algorithm 1). Severely increased albuminuria is defined as a measured (eg, with a 24 hour-urine collection) or estimated (eg, using a random urine albumin-to-creatinine ratio [ACR]) albumin excretion ≥300 mg/day. In practice, the majority of patients with diabetes with hypertension and DKD are treated with an ACE inhibitor or ARB, even if severely increased albuminuria is absent (ie, even if urine albumin excretion is <300 mg/day). However, while these drugs are more beneficial than other antihypertensive agents in patients with albuminuric DKD, they do not have clear advantages over calcium channel blockers or diuretics among those without albuminuria. (See 'Severely increased albuminuria: Treat with angiotensin inhibition' above.)

Combination therapy with both an ACE inhibitor and an ARB, or combining one of these drugs with a renin inhibitor, should be avoided.

●In patients with type 2 diabetes who have DKD and severely increased albuminuria (as defined above) despite angiotensin inhibition, we recommend treatment with a sodium-glucose cotransporter 2 (SGLT2) inhibitor (Grade 1A) (algorithm 1). We also suggest use of an SGLT2 inhibitor in patients with DKD who have lower levels of urine albumin excretion (Grade 2B). The SGLT2 inhibitor is typically added to the patient's existing glucose-lowering regimen since these drugs have weak glucose-lowering effects in patients with reduced kidney function. (See 'Type 2 diabetes: Treat with additional kidney-protective therapy' above.)

Initiating SGLT2 inhibitors should generally be avoided among patients with an estimated glomerular filtration rate (eGFR) <20 mL/min/1.73 m² (although they can likely be continued among patients whose eGFR ultimately falls below this threshold).

SGLT2 inhibitors increase the risk of genital infections by two- to fourfold (primarily vulvovaginal candidiasis) and have been associated with Fournier's gangrene in rare cases. Thus, patients with a prior history of or risk factors for genital infections may reasonably choose to not take an SGLT2 inhibitor.

SGLT2 inhibitors are not appropriate for use in patients with type 1 diabetes and kidney disease.

●Among patients with type 2 diabetes who have measured or estimated albuminuria ≥30 mg/day despite an ACE inhibitor (or ARB) and an SGLT2 inhibitor (or if an SGLT2 inhibitor is not tolerated), we suggest treatment with a nonsteroidal selective mineralocorticoid receptor antagonist (MRA; specifically finerenone) (Grade 2C), where available. However, finerenone should generally be avoided in patients who have a serum potassium >5 mEq/L or eGFR<25 mL/min/1.73 m².

●Besides SGLT2 inhibitors (which have a weak glucose-lowering effect, particularly in patients with reduced eGFR), the glucose-lowering drugs with the strongest evidence of benefit on cardiovascular and kidney outcomes are the glucagon-like peptide 1 (GLP-1) receptor agonists. (See 'Type 2 diabetes: Treat with additional kidney-protective therapy' above.)

●Patients with DKD should ideally be monitored every three to six months, with assessments of blood pressure, volume status, eGFR, serum potassium, and A1C, and an evaluation of urine albumin or total protein excretion (usually a random urine ACR). Reasons for referral of patients with DKD to a specialist nephrology service are similar to those for patients with other causes of CKD, including advanced CKD (eGFR <30 mL/min/1.73 m²), heavy albuminuria, rapid loss of kidney function, resistant hypertension, evidence of an inflammatory kidney disease (eg, hematuria and/or sterile pyuria), and difficult-to-manage complications of CKD (eg, hyperkalemia, anemia). (See 'Monitoring during therapy' above.)